This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Type 2 diabetics can have inadequate control of hyperglycemia despite the use of insulin plus several oral hypoglycemic drugs and lifestyle changes. Exenatide is a 39 amino acid polypeptide that is a receptor agonist for the endogenous incretin hormone called glucagon-like peptide-1 (GLP-1). Incretins increase pancreatic insulin secretion in response to elevations in glucose (hyperglycemia). Animal and human studies suggest several mechanisms of action: (i) enhanced insulin secretion in response to feeding and glucose elevation;(ii) suppression of inappropriately elevated glucagon secretion;(iii) decreased rate of gastric emptying and so slowed the rate of glucose delivery;(iv) reduced food intake, and, unlike insulin (v) weight reduction. The drug was efficacious in over 30 human studies lasting up to 132 weeks (studies summarized on page 20 of drug brochure). Decreased HbA1c was used as the primary efficacy measure. Exenatide decreased HbA1c in an equivalent fashion to insulin, but caused weight reduction unlike the weight gain associated with insulin.